Genetic Variant NM_139281.3:c.26C>A (chr5-111092482-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_139281.3(WDR36):c.26C>A(p.Thr9Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

WDR36
NM_139281.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

Variant links:

Genes affected

WDR36 (HGNC:30696): (WD repeat domain 36) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Mutations in this gene have been associated with adult-onset primary open-angle glaucoma (POAG). [provided by RefSeq, Jul 2008]

WDR36 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060738236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR36	NM_139281.3 link	c.26C>A	p.Thr9Lys	missense_variant	Exon 1 of 23	ENST00000513710.4	NP_644810.2	Q8NI36
WDR36	XM_047416729.1 link	c.26C>A	p.Thr9Lys	missense_variant	Exon 1 of 21		XP_047272685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WDR36	ENST00000513710.4 link	c.26C>A	p.Thr9Lys	missense_variant	Exon 1 of 23	1	NM_139281.3	ENSP00000424628.3	A0A0A0MTB8
WDR36	ENST00000505303.5 link	n.162C>A		non_coding_transcript_exon_variant	Exon 1 of 15	5
WDR36	ENST00000515784.1 link	n.136C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251064

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000325

AC:

475

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

224

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000389

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000223

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000229

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.194C>A (p.T65K) alteration is located in exon 1 (coding exon 1) of the WDR36 gene. This alteration results from a C to A substitution at nucleotide position 194, causing the threonine (T) at amino acid position 65 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.034

T;T;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.65

.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.061

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.075

N;N;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.13

N;.;.

REVEL

Benign

0.16

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.24

MVP

0.32

MPC

0.032

ClinPred

0.061

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over